Nu-(4-amino-2-butynyl)-nu-alkylcarboxamides



United States Patent O ABSTRACT or THE DISCLOSURE N(4-tertiary-amino-2butynyl)N-alkylcarboxamides are prepared from theappropriate N-propargyl amide, formaldehyde and the appropriate amine.They have useful pharmacological properties, e.g., as stimulants of thecentral nervous system.

This invention relates to novel compositions of matter known in the artof chemistry as aminoalkynes and derivatives thereof and to methods fortheir preparation.

In one of its aspects, the invention sought to be patented resides inthe concept of a class of chemical compounds which I designate asN-(4-amino-2-butynyl)- N-alkylcarboxamides. I depict these compounds ashaving a molecular structure corresponding to general Formula I,

R C ONCHzCEC-CH2-N=B lower-alkyl Formula I wherein R is selected fromthe group consisting of H and lower-alkyl and N=B is a basic tertiaryamine moiety.

As used herein the term N=B means a basic tertiary amine moiety; thatis, the amino nitrogen atom bears two substituents which do notmaterially affect the basicity of the amine moiety as a whole, or thetwo substituents are joined to form a ring, with the Same result. Suchamines are well known to those skilled in the art. For example, it isknown that lower-alkyl groups, loweralkenyl groups, and cyclo-alkylgroups do not detract from the basicity of an amine when they replacehydrogen on the amine nitrogen. Moreover, it is known that cyclic amineswherein two of the valence bonds of the amine nitrogen atom are joinedby an alkylene bridge, forming a heterocyclic ring, are relativelystrong bases, and as such are suitable for the purposes of my invention.

'.Hence by the group -N=B, I mean amines which are preferably selectedfrom the group consisting of di(loweralkyl)-amino,N-lower-alkyl-N-lower-alkenylamino, di- (loWer-alkenyl)amino,N-lower-alkyl-N-cycloalkylamino, di(cycloalkyl)amino, N(phenyl-lower-alkyl)-N-loweralkylar'nino, pyrrolidino, piperidino,morpholino, thiamorpholino, 2,5-dimethylpyrrolidino, and the like.

As used herein, the term lower-alkyl means saturated, monovalentaliphatic radicals, including straight and branched-chain radicals, offrom one to six carbon atoms. For purpose of illustration only and notbeing limited thereto, lower-alkyl is represented by methyl, ethyl,propyl, isoproyl, butyl, tert.-butyl, sec.-butyl, amyl, hexyl and thelike.

As used herein lower-alkenyl means monovalent aliphatic radicals of fromthree to seven carbon atoms, which contain at least one double bond, andare either straight or branched-chain. Among lower-alkenyl radicals .areincluded, for purpose of illustration, allyl, methallyl, crotyl,I-(Z-hexenyl), and the like.

As used herein cycloalkyl, means cyclic saturated aliphatic radicals offrom three to eight carbon atoms.

For purpose of illustration the term cycloalkyl includes, but is notlimited to, cyclopropyl, cyclobutyl, 2-methylcyclobutyl, cyclopentyl,cyclohexyl, 4-methylcyclohexyl, cyclo-octyl, and the like.

As used herein phenyl-lower-alkyl means a monovalent radical consistingof a phenyl nucleus bonded to the rest of the molecule through adivalent lower-alkylene radical of from one to six carbon atoms. Thephenyl nucleus thereof may bear low molecular weight substituentswithout adversely affecting the ultimate properties of the compound as awhole, as further described below. For purpose of illustration, suchsubstituents are represented by lower-alkyl, lower-alkoxy,lower-alkylmercapto, halo, trifiuoromethyl, amino, and the like.

In another of its aspects, the invention sought to be patented residesin the concept of a class of chemical compounds which I designate asN-(4-amino-2-butynyl)- lactams. I depict these compounds as having amolecular structure corresponding to general Formula II,

Formula II wherein Y is a lactam radical bonded to the remainder of themolecule through the lactam nitrogen atom. Thus the radical Y isrepresented by the general formula,

wherein R is a divalent bridge having from three to five atoms in thechain. The divalent bridge is an alkylene radical which can beinterrupted by a hetero atom of the class consisting of --O, S, NH- andN(lower-alkyl). For purpose of illustration, the lactam group Y isexemplified by, but not limited to, the following: 2-oxopyrrolidino,2-oxopiperidino, 2-oxohexamethyleneimino, 3-oxomorpholino,3-oxothiamorpholino, 2 oxo-oxazolidino, 2 oxo-piperazino,4-methyl-2-oxopiperazino, and the like.

In Formula II, R and R can be the same or different and are selectedfrom the class consisting of H, loweralkyl, lower-alkenyl andphenyl-lower-alkyl, each as defined above.

In still another of its aspects, the invention sought to be patentedresides in the concept of a class of chemical compounds which Idesignate as N-(ami'no-aliphatic)- pyrrolidinones. I depict thesecompounds as having a molecular structure represented by the FormulaIII,

CHr-OHg N'0HgZcHT1 L A CHfl-C=O Formula III wherein A is a divalentbridging radical having from 5 to 7 atoms in the chain and Z is adivalent bridging radical having its valence bonds on adjacentcarbonatoms. The divalent bridging radical, A, is an alkylene radical whichcan be interrupted by a member of the class consisting of -O, S, NH, and

N(lower alkyl)- radicals. The group according to this definition, thusincludes for purpose of illustration, but is not limited to, thefollowing: piperidino, 4-methylpiperidino, hexamethyleneimino,heptamethyleneimino, morpholino, 2-methylmorpholino, thiamorpholino,piperazino, 4-methylpiperazino and the like.

The divalent bridge, Z, is an aliphatic chain having its valence bondson adjacent carbon atoms and is saturated or unsaturated. The term Zthus represents, alkylene, for example,

CH3 CH3 C2115 and the like; vinylene, for example,

OH=CH, -C=OH, -c c- (1H CH3 (IE Formula 1V wherein A is a member of thegroup consisting of a divalent alkylene radical of from two to fourcarbon atoms and an ortho phenylene radical and N=B is as defined above.In Formula IV, the group is a cylic imide radical of from five to sevenring members. The cyclic imide radicals are illustrated by, but notlimited to, succinimido, glutarimido, adipimido, pyrotartarimido,2,3-dimethylsuccinimido, phthalimido, methoxyphthalimido,S-methylphthalimido, 4,5,6,7-tetrachlorophthalimido, 4butoxyphthalimido, 5 methylmercaptophthalimido, 4-bromophthalimido, andthe like.

In still another aspect, the invention sought to be patented resides inthe concept of a class of chemical compounds which I designate asN-(4-amino-2-butynyl)- heterocyclic amines. I depict these compounds ashaving a molecular structure corresponding to Formula V,

Formula V wherein N=B is an amine group as defined above for Formula I,and X is a member of the group consisting of S, O, CH=CH, -N=N, and CH-CH In this aspect, the compounds of the invention are1,4-diamino-Z-butynes, wherein one of the amino moieties is a tricyclicheterocycle selected from the group consisting of phenoxazinyl, 1Ophenothiazinyl, 5 dibenz[b,f]- azepinyl, l1H-dibenzol[1,2,5]triazepinyl,and 5-(10,11- dihydro) -dibenz[b,f] azepinyl.

Formulas IV and V encompass compounds which have one or two benzenerings incorporated therein. Here and elsewhere throughout thisspecification, it will be understood that the benzene ring can beunsubstituted, or it can hear one or more substituents of low molecularweight and of such nature that they do not interfere or take part in thepreparative reaction.,When substituted, the benzene ring has from one tofour substituents which can be in any of the available positions of thering, and

where more than one substituent is present, they can be the same ordifferent, and they can be in any of the various position combinationsrelative to each other. The

substituents preferably have a molecular weight of less than 150.Examples of such substituents, for the purpose of illustration, butwithout limiting them thereto, include lower-alkyl, lower-alkoxy,lower-alkylmercapto, loweralkylsulfinyl, lower-alkylsulfonyl, halogen,nitro, tn'fiuoromethyl and cyano, wherein lower-alkyl is as prew'ouslydefined.

The manner and process of making and using my invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

The final products of the foregoing aspects of this invention, asexemplified by general Formulas I, II, III and IV, can be prepared bythe following general procedures. A carboxylic acid amide or imidehaving at least one hydrogen atom attached to the nitrogen atom thereofis caused to react in an inert solvent at a temperature less than 3 0C., preferably about room temperature, with a propargyl halide, forexample propargyl bromide, in the presence of a strong base to form theN-propargyl amide (or imide). The nature of the inert solvent is notcritical, but I prefer to use toluene, benzene, or ether. Theintermediate N-propargyl amide (or imide) is then caused to react withformaldehyde and an amine, which contains at least one hydrogen atomattached to the nitrogen atom thereof, under conditions well-known tothe art for carrying out the Mannich reaction with acetylenes. I preferto employ a trace of cuprous chloride as a catalyst in the Mannichreaction.

The compounds of the invention represented by Formula V (i.e., bearing atricyclic amine structure) are prepared in the same manner as the abovecompounds. That is, the tricyclic amine, bearing a secondary aminenitrogen, is caused to react with propargyl bromide in the presence of astrong base (acid acceptor) and the N-propargyltricyclic amine is thencaused to react with formaldehyde and a secondary amine in theconvention Mannich reaction procedure.

In the above procedure, the nature of the strong base is not critical,but it must be at least as strong a base as sodium hydroxide. Examplesof suitable strong bases include sodium hydride, sodium amide, lithiumamide, sodium ethoxide, potassium tert.-butoxide, tetramethylammoniummethoxide, sodium hydroxide, and the like.

The final products of my invention are usually obtained in their freebase form as yellowish or colorless oils which may be distilled atreduced pressure without decomposition. While the compounds are basicsubstances and can form acid-addition salts or quaternary ammonium saltswith strong acids or organic esters thereof, respectively, I have foundthat the salt forms are difficult to obtain in crystalline form. Itherefore prefer to isolate the products of my invention in their freebase form.

The final products of my invention, as exemplified by general FormulasI, II, III, IV and V are useful as pharmacodynamic agents. Inparticular, compounds in this group have been found useful for theirstimulating effect on the central nervous system, as evidenced byreversal and prevention of reserpine-induced ptosis in mice. Compoundsin this group are also effective central nervous system depressants, asevidenced by hexobarbital potentiation and antagonism towardpentylenetetrazole activity in mice. In the central nervous systemdepressant tests, compounds in this series showed a superior spectrum ofactivities and gave more reliable results than did reference compoundsin the art.

Examination of the compounds produced by the processes described above,and more particularly described-in the examples below, by nuclearmagnetic resonance ,and infrared spectographic analysis reveals spectraldata con-. firming the molecular structure set forth herein. Thesephysical characteristics, taken together with the nature of the startingmaterials, the mode of synthesis, and the correspondence of calculatedand found values of elemental analyses of representative samplespositively confirm the structure of the compositions sought to bepattented.

The best mode contemplated by the inventor of, carrying out hisinvention will now be set forth as follows:

Example 1A N-methy l-N-propargy lacetamide To a mixture containing 23 g.(0.5 mole) of sodium hydride (52% suspension in mineral oil) in 600 ml.of toluene was added a solution containing 36.5 g. (0.5 mole) ofN-methylacetamide over a period of 45 min. in a nitrogen atmosphere. Themixture was refluxed for 2.5 hr. and allowed to cool to roomtemperature. A solution containing 60.0 g. of propargyl bromide in 100ml. of toluene was added dropwise over .a period of 1.5 hr. The mixturewas allowed to stir at room temperature overnight. It was then filtered,and the filtrate solvent was removed under reduced pressure. The residuewas passed through a chromatographic column packed with silica gel. Theproduct was eluted with a 1:1 ether-hexane mixture. Upon removal of thesolvent the residual oil was distilled and redistilled. The product,N-methyl-N-pro pargylacetamide, boiled at 53 at 0.8 mm.; N =1.48l4.

Example 1B. N methyl N-4-pyrr0lialinb-Z-batynylacetamide Under anitrogen atmosphere, a solution containing 13.0 g. (0.12 mole) ofN-methyl-N-propargylacetamide, 5.8 g. of paraformaldehyde, 10.5 g. (0.15mole) of pyrrolidine and a trace of cuprous chloride in 80 ml. ofdioxane was refluxed for 5 hrs. and allowed to stand overnight. Themixture was filtered and the filtrate solvent removed under reducedpressure. The remaining oil was distilled and redistilled givingN-methyl-N-(4-pyrrolidino- 2-butynyl)acetamide, boiling .at 120 C. at0.03 mm.

Example 2A.N-propargylsuccinimide To a solution containing 54 g. (1mole) of sodium methoxide in 400 ml. of methanol was added a solutioncontaining 99 g. (1 mole) of succinimide in 400 ml. of methanol under anatmosphere of nitrogen. During the addition, the reaction mixture waskept at about 25 C.

by means of a water bath. The mixture was then refluxed for 30 min. andcooled to 20 C. with a water bath, giving a clear solution of sodiumsuccinimide. To this solution was added dropwise a solution containing132 g. (1.1 moles) of propargyl bromide in 100 ml. of methanol over aperiod of 1.5 hrs. The mixture was allowed to stir overnight and thesolvent was removed under reduced pressure. Chloroform was then added tothe residual oil, and the sodium bromide which precipitated was removedby filtration. The filtrate was passed through a chromatographic columnpacked with silica gel, and the product was eluted with methanol andether. After removal of the solvent, the residual oil was distilledgiving N-propargylsuccinimide, which boiled at 98 C. at 0.03 mm, N'=1.5402.

Example 2B.--N-[4-(J-pyrr0lidinyl)-2-butynyl]- succinimide Following theexample given in Example 1B, 19.1 g. (0.15 mole) of Npropargylsuccinimide was caused-to react with 6.3 g. of paraformaldehydeand 14.2 g. (0.2 mole) oTfiyrrolidine in 100 m1. of dioxane in thepresence of a trace of cuprous chloride. The reaction was refluxed for 5hrs. and allowed to stand overnight. After filtration of the reactionmixture and removal of the solvent from the filtrate, the residual oilwas distilled to give N-[4-( l-pyrrolidinyl)-2-butynyl] -succinimideboiling at 155 C. at 0.04 mm. This product solidified, and afterrecrystallization from ether, melted at 93.0 to 94.0 C. (corn).

Example 3A .-2-chl0r0-10-propargylphenothiazine To a solution containing0.2 mole of butyllithium in 350 ml. of absolute ether (prepared in situunder nitrogen) were added 46.5 g. (0.2 mole) of 2-chlorophenothiazinewhile the mixture was maintained at 10 C. The reaction mixture was thenallowed to stir for fortyfive minutes at 0 C. To the resulting solutionof 2- chloro-lO-phenothiazinyllithium were added 30 g. (0.25 mole) ofpropargyl bromide in 30 ml. of absolute ether. This reaction mixture wasallowed to stir at room temperature overnight. After quenching withdilute hydrochloric acid, the ethereal phase of the reaction mixture waswashed with water and dried over anhydrous calcium sulfate. Upon removalof the solvent a semi-solid mass of crude2-chloro-l0-propargylphenothiazine remained. Recrystallized frommethanol and from etherhexane, pure 2-chloro-10-propargylphenothiazinemelted at 112.0-115.0 C. The structure was confirmed by rmclear magneticresonance spectroscopy.

Example 3B.2-ch Zora-1 0- [4 1 -pyrr0lidinyl -2-butynyl] phenothiwzineFollowing the procedure given in Example 13,2-chloro-lO-propargylphcnothiazine (21.7 g.; 0.08 mole) was caused toreact with 3.8 g. of paraformaldehyde and 7.1 g. (0.1 mole) ofpyrrolidine in the presence of a trace of cuprous chloride in dioxane.Recrystallized from etherhexane, the pure2-chloro-10-[4-(1-pyrrolidinyl)-2-butynylJ-phenothiazine thus obtainedmelted at 48.050.-0 C.

The following compounds are obtained by the method given above:

10,11-dihydro-5-[4-(l-pyrrolidinyl)-2-butynyl] 5H dibenz[b,f] azepine,melting at 53.4-54.2 C.;

5- [4- (butylmethylamino) -2-butynyl]-10, l-l-dihydro-SH- dibenz[b,f]azepine, a yellow oil, n 1 .5 870;

10,1 1-dihydro-5-[4-(dimethylamino)-2-butynyl]-5H- dibenz[b,f] azepine,melting at 55 .6-5 6.8 C.;

5- (4-piperidino-2-butynyl) -5H-dibenz b,f] azepine;

11- (4-pyrrolidino-2-butynyl) -1'l-H-dibenzo 1,2,5 triazepine;

10-('4-morpholino-2 butynyl)phenoxazine; and

10-[4- (diisopropylarnino -2-butynyl]-2-trifluoromethylphenothiazine.

Example 4 .N -[4 1 -p'yrr0lidinyl) -2-butenyl]-pyrrolirlinone A solutioncontaining 24.7 g. (0.12 mole) of 1-(4-pyrrolidino-Z-butynyl)-2-pyrrolidinone dissolved in 250 ml. of pyridinewas hydrogenated in a bottle-type hydrogenator over 5 g. of 2%palladium-on-strontium carbonate catalyst. When the theoretical quantityof hydrogen was absorbed, the catalyst was removed by filtration and thesolvent was removed under reduced pressure. Upon distillation andchromatographic separation, the product,N-[4-(l-pyrrolidinyl)-2-butenyl]-pyrrolidinone, was obtained as a clearoil distilling at 107 C. at 0.05 mm.

Example 5 .N- [4- 1 pyrrolidinyl -butyl -2-pyrr0liainone A solutioncontaining 21.0 g. (0.10 mole) of 1-(4-pyrrolidino-Z-butynyl)-2-pyrrolidinone dissolved in 205 ml. of absoluteethanol was hydrogenated in a bottletype hydrogenator over 0.6 g. ofplatinum oxide catalyst. When the theoretical quantity of hydrogen wasabsorbed, the catalyst was removed by filtration and the filtrate wasremoved under reduced pressure. Upon distillation, the product, N-[4(l-pyrrolidinyl)-butyl]-2-pyrrolidinone, was obtained as a clear oilboiling at 118 C. at 0.05 mm.; N =1.4922.

Example 6.1-[4-(diethy.lamino) -2-butynyl]pyrr0lidine Following theprocedure given in Example IE, 7.8 g. (0.07 mole) ofdiethylpropargyla-mine, 3.8 g. of paraformaldehyde, 5.7 g. (0.08 mole)of pyrrolidine, and a trace of cuprous chloride in ml. of dioxane werereunrrm) STATES PATENT OFFICE CERTIFICATE CORRECTION Patent. No;3,354,178 November 21, 1967 William B. Dickinson It is certified thaterror appears in the above identified patent and that said LettersPatent are hereby corrected as shown below:

Column 5, line 26, "Nmethyl-N-4-" should read N- methyl-N-(4- Column 8,line 52, "N-[4-(3-pyrrolin-l-yl- 2-butynyl]-2 pyrro1idinone" should readN-(4-pyrrolidino- Z-butynyl)S-thiamorpholinone Column 9, line 12, "N-4-should read N-[4- line 13, "N[4-N- should read N-[4-(N- Column 10, lines18 to 20, the formula should appear as shown below:

Ca -CH R-CO-N-CHZ-CEC-CH -N lower alkyl an -0H Signed and sealed this13th day of January 1970.

(SEAL) Attest:

Attesting Officer Commissioner of Patents

1. A COMPOUND OF THE FORMULA R-CO-N(-LOWER-ALKYL)-CH2-C*C-CH2-N=BWHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF H AND LOWER-ALKYL ANDN=B IS A BASIC TERTIARY AMINO RADICAL SELECTED FROM THE GROUP CONSISTINGOF DI(LOWER-ALKYL) AMINO, N-LOWER-ALKYL-N-LOWER-ALKENYLAMINO,DI(LOWERALKENYL)AMINO, N-LOWER-N-CYCLOALKYLAMINO, DI(CYCLOALKYL)AMINO,N-(PHENYL-LOWER-ALKYL)-N-LOWER-ALKYLAMINO, PYRROLIDINO, PIPERIDINO,MORPHOLINO AND THIAMORPHOLINO. 5.N-METHYL-N-(4-PYRROLIDINO-2-BUTYNYL)-ACETAMIDE.